1. Field of the Invention
This invention relates to the preparation and use of azabicycloalkane phenyl substituted alkane carboxylates, including pharmacologically useful compositions thereof, as anticholinergic agents.
2. Prior Disclosure
Nerve gas poisons function by irreversibly inhibiting acetylcholinesterase (AChE). This leads to a build up of excess acetylcholine resulting in overstimulation of both the peripheral and central nervous system. A single acute dose of a nerve gas can lead to death with the primary cause of death being respiratory failure.
The organophosphate nerve agents GD (soman), GB (sarin) and VX are extremely potent cholinesterase inhibitors (anticholesterases). Like other organophosphate poisons, they owe their biological activity to phosphylation of serine hydroxyl at the active site of the enzyme acetylcholinesterase, thereby deactivating it in an essentially irreversible manner. As a consequence of this deactivation, the neurotransmitter acetylcholine accumulates at cholinergic sites, producing an effect roughly equivalent to continuous stimulation of cholinergic fibers throughout the central and peripheral nervous systems.
Standard therapy for organophosphate nerve agent poisoning is based on the concurrent administration of an anticholinergic agent to antagonize the effects of the accumulated acetylcholine and a cholinesterase reactivator to dephosphylate the inhibited enzyme. The standard anticholinergic agent used in therapy is atropine sulfate. Pyridinium oximes such as 2-[(hydroxyimino)methyl]-1-methylpyridinium halide (2-PAM) are the most studied cholinesterase reactivators. Various other drugs have been examined as adjuncts to this therapy in order to control the convulsions which are a side-effect of the poisoning, to assist in countering respiratory failure, or because of their antimuscarinic properties. Specific examples are benactyzine, and aprophen. Atropine is known to antagonize the muscarinic effects of acetylcholine and is the best-known of the so-called antimuscarinic agents. The usefulness of atropine has stimulated the study of other antimuscarinic agents as potential treatment drugs for anticholinesterase poisoning.
Since the ionic nature of many cholinesterase reactivators limits their efficacy to the peripheral nervous system, the anticholinergic drugs are the primary source of protection for the central nervous system. The practical usefulness of the anticholinergic drugs is limited by their central nervous system activities and their toxicities.
There is a need for new effective anticholinergic agents for the pre-treatment (prophylaxis) against and treatment of organophosphate nerve agent poisoning. Like atropine, such agents must exhibit a higher affinity than acetylcholine for the receptor sites. In addition, neutral molecules with some degree of lipid solubility are preferred because of their ability to penetrate the bloodbrain barrier and protect the central nervous system. Benactyzine and aprophen are two examples of such compounds. Compounds which are more effective antimuscarinic agents than atropine, benactyzine, and aprophen are potentially good candidates for therapeutically useful drugs.